Radio Cade

Targeted Natural Enzymes to Treat Chronic Inflammation

May 22, 2019 Greg Hudalla and Ben Keselowsky Season 1 Episode 33
Radio Cade
Targeted Natural Enzymes to Treat Chronic Inflammation
Radio Cade
Targeted Natural Enzymes to Treat Chronic Inflammation
May 22, 2019 Season 1 Episode 33
Greg Hudalla and Ben Keselowsky

Our 2019 Cade Prize winners, Greg Hudalla and Ben Keselowsky, have invented a new way to control inflammatory diseases such as arthritis. The method uses natural enzymes to suppress inflammation at the source, without the harmful side effects of medications.   Ben, a native of Tampa and a graduate of the University of South Florida, always enjoyed science and math and was inspired by his high school physics teacher. Greg, originally from Chicago, became interested in medicine after a serious knee accident at 18 ended his collegiate athletic career.   

Show Notes Transcript

Our 2019 Cade Prize winners, Greg Hudalla and Ben Keselowsky, have invented a new way to control inflammatory diseases such as arthritis. The method uses natural enzymes to suppress inflammation at the source, without the harmful side effects of medications.   Ben, a native of Tampa and a graduate of the University of South Florida, always enjoyed science and math and was inspired by his high school physics teacher. Greg, originally from Chicago, became interested in medicine after a serious knee accident at 18 ended his collegiate athletic career.   

Intro: 0:01
Inventors and their inventions. Welcome to Radio Cade a podcast from the Cade Museum for Creativity and Invention in Gainesville, Florida. The museum is named after James Robert Cade , who invented Gatorade in 1965. My name is Richard Miles. We'll introduce you to inventors and the things that motivate them, we'll learn about their personal stories, how their inventions work and how their ideas get from the laboratory to the marketplace.

Richard Miles: 0:39
Weekend warriors rejoice, your bad knees are about to get better. That is if the breakthrough by our guests today becomes widely available. People suffering from arthritis will have a brighter future. And before I mangle any more metaphors, welcome my guests, Greg Hudalla and Ben Keselowsky, both professors in biomedical engineering at the University of Florida. Welcome Greg and Ben .

Ben Keselowsky: 0:57

Greg Hudalla: 0:57

Richard Miles: 0:58
So this is actually personal for me because I've been a lifelong runner and just last year found out I have osteoarthritis, a word I couldn't even pronounce six months ago, much less define. So in between icing my knee and stretching, spending a lot of time at the physical therapist office, I come across your application of the Cade Prize. And so after the show, you'll both lay hands on me and I'll be good to go, right? It's simple, a few needles might be evolved , right ? So let's explain for our listeners in simple terms, what is the problem that you're trying to solve? And how does your invention do that?

Ben Keselowsky: 1:29
Our mission is to control inflammatory disease and we're motivated by the fact that inflammation underlies the onset, the progression and the pain associated with numerous diseases that affect millions of people. And so osteoarthritis is one of these that we're particularly interested in, in the U.S. 13% of the population is afflicted. That's over 40 million people with direct healthcare costs of over $80 billion per year. Current technologies include steroids and antibodies, and they're injected into the bloodstream and they're distributed throughout the body. And they're associated with terrible side effects, including infection, lymphoma, diabetes, and weight gain. And our technology works at the site of inflammation and it uses natural mechanisms that suppress inflammation. And so, we use an enzyme called IDO, Indoleamine dioxygenase, it breaks down an essential amino acid, tryptophan, into its product [inaudible] . And those two mechanisms, the local depletion of tryptophan and production of [inaudible] work together to quiet down inflammation. And so being able to suppress that inflammation allows tissue to return to healthy function.

Greg Hudalla: 2:51
So the key challenge for us when we began developing this technology was coming up with a strategy to place IDO at the site action and have it persist There for a useful duration of time. Um , so if you were to say, inject the drug directly into the tissue of interest, it would be gone within minutes to hours. So you don't really get a lot of activity or efficacy from a drug.

Richard Miles: 3:14
Greg, if I can interrupt that's the current standard of care, right? That's what most people do though. They'll go in, for instance, with osteoarthritis, they'll go in to get a shot of what is a cortisone or something like that, right?

Greg Hudalla: 3:22
Right.Yeah, so they'll either get a topical treatment right on the surface of the skin, in which case the steroid can penetrate into the joint and have some effect, or they'll get a localized injection, or they'll have say an intravenous infusion of drug that's coursing throughout the entire body. So, what we sought to do was develop an approach by which you can inject the drug into the tissue site, and it would persist as opposed to diffusing away and losing action at the site of interest. So to do this, we developed a technology that we've dubbed GATOR, which stands for Galectin Anchors for Therapeutic Enzyme Retention. Specifically, we link IDO our therapeutic enzyme to galectin three, a protein that binds to sugars that decorate every tissue within your body by binding to tissue sugars. Galectin three anchors IDO at the site of injection. So this prevents the diffusion of the drug through the tissue. And this gives us a much longer duration of action of drug at the site of interest. So for example, our version 1.0 of IDO GATOR persists at the injection site for upwards of seven days. Whereas again, conventional drugs say if we were to inject IDO into the tissue directly, it would be gone within minutes to hours. So in terms of moving the technology forward, we have demonstrated preclinical efficacy of IDO GATOR, and a couple of models. So the first is osteoarthritis as was alluded to at the onset of our show today. Um, in these cases, we've been able to demonstrate that injection of IDO GATOR into the joint that's afflicted with osteoarthritis will reduce pain that's sensed by the host. It will also tamp down inflammation, which in turn will prevent further progression of the disease. And a striking sort of observation here is that injection of IDO GATOR can restore normal gait in the patients . So a patient that's experienced some degree of limping that limp will be diminished following injection of the drug into the joint. The other space where we have really exciting data is in the area of periodontal disease. So a non resolving chronic inflammation in a tooth. And what we've demonstrated to date is that by injecting IDO, IDO GATOR into the site of disease, that again, we can suppress inflammation as a result of turning down that inflammation. We can prevent the bone loss, that's a hallmark of the disease, which would ultimately lead to the need for the tooth to be extracted or removed. So by getting ahead of the inflammation, we're not getting ahead of the disease progression

Richard Miles: 5:42
So far, I'm loving this. I mean, it sounds like great news. And I neglected mention at the top of the show that to , to congratulate you on advancing from the Cade Prize, sweet 16 round to the final four round. So congratulations to both of you. -Thank you very much. Tell me, does your current research indicate, is there the possibility that you could extend this even beyond say seven days? And is there also the possibility that you mentioned there would be like in the case of say knees, injections, is there a topical patch or application possibility in this?

Greg Hudalla: 6:11
Yeah, so I'll touch on the first question, which is, is there a way to extend the duration? So we haven't demonstrated it yet with IDO G, but we have developed a model platform in which we can achieve residence time or duration of action, upwards of about 14 to 17 days at the injection site. So in order to do this, we play sort of a biochemistry trick. So most of your listeners are probably familiar with Velcro, right? And Velcros two material surfaces that interact through a series of hooks and eyes, right? And if you were in a vision , one hook interacting with one eye, you can pull it apart pretty easily, but as you start to link multiple hooks and eyes together, you significantly strengthened the interaction at that interface, the interaction between the two pieces of Velcro. So what we do essentially, as we increase the number of galectin three binding sites, and we take our protein of interest or therapeutic interest say IDO, and now, instead of linking it to one copy of our galectin three anchor, we can link it to two or three or four copies of our collecting three anchor. And so this acts in a census molecular Velcro now, instead of having one site of interaction, you have multiple sites of interaction by adding these sites of interaction together, you can strengthen the anchoring phenomenon that we see occur. And so again, we can go from our flagships seven day formulation to formulations that should persist for weeks at the injection site .

Richard Miles: 7:29
So before we talk about the commercial path that you'd like to see this travel, let's talk a little bit about the approval process, right? Because what little I know of medical drugs of any sort of medical devices, there's this very long convoluted FDA approval process that lasts like 100 years, right ? Roughly right . Maybe 98. It's just going to be tough to get through the approval process. Ben, you want to take a stab at that?

Greg Hudalla: 7:49
So as you mentioned, this would classify as a drug. And so with that comes some unique challenges in the FDA translation space. So first maybe a bit of history. So our therapeutic is an enzyme and enzymes are actually the first class of proteins that were pursued as biologic drugs. So as early, as about the 1950s, when scientists first started developing a real handle on what enzymes do and the roles that they play, and then being able to extract them from living systems, they were really attractive drug candidates because they catalyze reactions they'll speed, a reaction up they're essential for basically every biological reaction that happens in our bodies. And so the idea is that unlike a small molecule in which you deliver a very high dose, in principle, you can deliver a little bit of enzyme and it will go a very long way because it will continue acting on drugs fast forward about 30 years into the future, and enzymes have been outpaced by biologic drugs that we hear a lot more about. And some things like monoclonal antibodies. And the reason why is because of the fact that a little bit of enzyme goes a long way. If they leave the site of intended action, they can catalyze reactions offsite, and this can lead to unwanted side effects. So again, that was one of the major drivers behind our anchoring technology now onto the sort of translational efforts or the , what we see as the translational path for IDO GATOR, one of the benefits of our system. So let me remind everyone that what our technology is really based on is what we know of sort of a peanut butter and jelly or chocolate and peanut butter. We take a really promising enzyme drug, and we link it to this anchoring domain, galectin three. And so we've taken two proteins and we've physically stuck them together to make a new molecule , um , on some level that presents a series of challenges. But the benefit here is that IDO is a protein that's expressed within our bodies . So we're naturally tolerant to that enzyme being around galectin three is also a protein that is expressed within our bodies. So we're naturally tolerant to galectin three being around. So we envision from a safety profile, that IDO of galectin three will be relatively safe from the perspective of it's tolerance by your immune system. The other benefits of our system that sort of speak to this safety features are that because we're delivering IDO GATOR locally, we can significantly reduce the dose. So even if a little bit of drug does leave the site of intended action and get into circulation, move into another tissue, the amount of enzyme that's, there is so low that it's unlikely to have significant side effects that one might experience if they were to deliver the same drug systemically. So, from the perspective of the molecule itself and sort of entry into the human space, we see those as being real advantages. There's one more unique feature of our technology that I want to touch on too , which sets it apart from a lot of biologics that go through the preclinical pipeline and then try to make the transition into the clinical or human use space. And that is that galectin three, the anchoring domain in our technology interacts with sugars that are decorating human tissues, but these sugar molecules are conserved from mouse to man. So what that means is , is in principle, there will be no re-engineering of the drug that's required. So your listeners may have heard of humanized antibodies in the past. So this is an antibody that's raised in an animal host. And then the domain that's necessary for binding to sites in our tissue is maintained. It's moved over from the animal antibody into a human antibody to make it safer, make it more tolerated within human systems. We wouldn't need to go through that process. So we see on one level, a clearer translation from the preclinical studies that we're doing now into the clinical space, but we also see this as another potential business opportunity. And that is that we could in theory, use this same therapeutic in veterinary medicine applications. So osteoarthritis, periodontal disease, the two spaces in which we've been evaluating efficacy now , um , are things that afflict companion pets all the time, right? My dogs have had teeth extracted because of , of periodontal disease. And I know of a significant number of friends who have dogs and cats that's that have experienced osteoarthritis in their hips and their knees. As they get older, they receive a lot of the same conventional treatments that humans do, injections of steroids or injections of antibodies because of the fact that both IDO and the galectin three anchoring domain are conserved across mammalian species and the mechanisms by which they work are conserved across mammalian species. We really think there's an opportunity here to translate into the vet product space first, and then use that to really springboard into the human clinical use.

Richard Miles: 12:13
So let's talk about the business side a bit. Now, could you describe for me what sort of your game plan is now? I mean, are you both going to quit your jobs? One of you clean out your garage? You'll be for like Steve Wasnic was next Steve jobs, right. You'll be mixing enzymes in the basement or is there a different, a better path available?

Ben Keselowsky: 12:27
Yeah. So this gets into the question of what is it that people should do when they're trying to start a new company, and it's really about finding the right team. So finding the right team members and that's where we're at. So, we are looking for business people. We're looking for investing partners to really help drive this forward with vision, with experience. This is the stage we're at. We're trying to find partners to help drive this forward.

Richard Miles: 12:54
Oh , so still very early stage. Do you have patents on this technology?

Ben Keselowsky: 12:57
We're pending. Yes, we do. We're very lucky to have excellent support from the office of technology licensing here at UF, and we are pursuing patents in U.S., Canada, Europe, Japan, and Australia and Australia. Thank you.

Richard Miles: 13:11
So one of the things our listeners find interesting, at least I find it interesting is the personal backgrounds of the inventors that we have on the show. So Ben, maybe starting with you, if you could talk a little bit about where you're from, what were some of your early influences? How'd you end up in North central Florida doing some research?

Ben Keselowsky: 13:26
Sure. Yeah. So I am born and raised in Florida from Tampa.

Richard Miles: 13:31
So you're a long way from home, right?

Ben Keselowsky: 13:33
95 miles or something. That's right. So growing up in Tampa, I went to USF and studied there. And then I moved all the way up North to Atlanta for grad school and then moved back down to Tampa. So I was,

Richard Miles: 13:44
Winters were too cold for up there?

Ben Keselowsky: 13:45
Yes, they dragged on and on in Atlanta. So I was very happy to get my family close. We love the small college town. You have mentioned. We were just across the street at the festival. And so we enjoyed the small college town and UF is a fantastic place to be. Our department is centrally located with the health sciences, the teaching hospital, the veterinary medicine, the rest of engineering. We have a really great location where we are in . Fantastic.

Richard Miles: 14:13
Did you always want to go into an engineering or science related field? What were you like as a kid? Were you a good student? Teacher's pet? Spill the beans here.

Ben Keselowsky: 14:20
I really quite enjoyed science and math. And my dad was a retired mechanical engineer, worked at TECO Tamp Electric Cooperative. He'd take me to the power plant and show me the boilers and everything that , how it works and teach me how combustion engines work. So, yeah, I was pretty nerdy and enjoyed things like that. It was basically told I'm doing well in this. I should think about engineering. That was your parents telling you that teachers telling you that was my father. Um, and actually in high school, I looked up to my physics teacher a lot. He was fantastic. Terry Adams, he made things very fun. And the group in the class had a lot of fun trying to learn these concepts together and really enjoy the creativity and the teamwork, which is fantastic. Greg and I came together on this chocolate and peanut butter concept just by chatting because we're right next door . Our offices are running door to each other, but growing up, I was kind of did well in math and science and enjoyed it a lot. I enjoyed the arts too, but now kind of my outlet is the creativity with science and technology.

Richard Miles: 15:27
Greg, your turn, were you the sort of kid that we're dissecting frogs when you're three years something, tell us about your upbringing.

Greg Hudalla: 15:33
So I grew up in and then just outside of Chicago. So I'm a bit farther away from home. I did my undergrad at the Illinois Institute of technology and then grad school in Wisconsin so much like Ben made a pretty short commute from home. And then I moved back to Chicago and my entire family, my entire extended family is still in the greater Chicago land area. So when I left for Madison and then came back, they thought, all right , you've done it. You've seen the world. You know , there's Chicago, it's the greatest city on earth.

Richard Miles: 15:57
Wisconsin, how much further can you go? I mean come on.

Greg Hudalla: 16:00
And then , uh , Ben was on the hiring committee when I was applying for jobs and University of Florida popped up on my radar. And you could sort of hear the needle scratch if you will, or the tire squeal in the minds of all of my family members, as I tried to explain to them that we were going to pick up and move to Gainesville, but you know, it's been great. It's a quintessential American college town and it's been a really terrific experience in the few years that I've been here. So getting back to a little bit of my sort of pre academic time. So I was always a good student, but when I went to college, I didn't really have a clear vision of what it was that I wanted to do. So, I'm the son of an iron worker and a court reporter. And for them, college was a big deal putting my brother and I into school and seeing us through to the finish line was a huge deal for the two of them. But I was flexible. And like I said, sort of lacking vision when I first went to college. And so my freshman year I was actually a college athlete. So I was playing on the university soccer team and three games into my freshman year. I suffered an injury to my knee that resulted in a significant amount of cartilage. So damage on the, about the size of a silver dollar cartilage had detached from my femur. So I'm in 18, 19 year old kid. At this point in time, I went from pretty much not having osteoarthritis to having extremely advanced osteoarthritis,

Richard Miles: 17:16
So this really is personal for you.

Greg Hudalla: 17:17
30 seconds. Right? And so when we went to the orthopedic surgeon, the suggestion at the time was we have to take the cartilage out and we're probably going to need to give you a total knee replacement. And again, I'm a 19 year old kid at this point in time,

Richard Miles: 17:30
Not the typical knee replacement surgery candidate .

Greg Hudalla: 17:32
Exactly. Right? And this is the early two thousands when total knee replacements don't have a particularly long lifespan . And so insurance wasn't happy. My parents weren't happy. I wasn't happy. The surgeon wasn't happy. And so initially they had done a microfracture procedure to try and restore , uh , send me the cartilage that was still relatively healthy at the site. And some time was put into, let's try to find an alternative approach, some other way to deal with this. And so maybe six to nine months later, we're meeting with the orthopedic surgeon. And he says, I think you're a good candidate for a brand new technology. It's technology known as Carticel that was pioneered by Genzyme in which they take a biopsy of cartilage cells from a healthy site in your body. And they send them out to a lab. They grow them up and they reimplant those cells back into your tissue . So it's a way to save the joint, save the bone, and ideally provide me a longer timeframe before I might need a total knee replacement. Now I'm 18 or so 19 years out from this procedure. And I still have my original knee, but it was at that moment, that was when the light bulb went off for me. And I said, I want to know who does this right? Who develops technologies like this ? What career path do you follow? Where you can work on things where you can have this sort of impact on someone's quality of life. And that was when I was introduced to the world of biomedical engineering. And from that moment forward, I said, this is what I want to do. I'm going to study engineering, go to graduate school. And ultimately I want to be running my own academic research lab somewhere.

Richard Miles: 18:55
Wow, that's an amazing moment of clarity for an 18 year old. So refresh my memory. This would result of a hit on the field, or how did this happen?

Greg Hudalla: 19:02
Yeah, so I,

Richard Miles: 19:03
So you need to go back and thank that guy who took you out, right? Like, oh he gave me direction.

Greg Hudalla: 19:07
So it was me that, you know, the fault is entirely on me. I remember going in for the slide tackle and feeling the moment of pain and thinking, this is it, this is what's happened. What's going on. It was a game changing experience.

Richard Miles: 19:17
So the two of you are still in the thick of your academic careers. And I realized I have to talk to you . You're you're older than I thought you were. I think part of it's by the time you hit your mid fifties, everybody looks young, right? So I was going to say, well, you don't have much experience to share, but clearly you actually do, in terms of wisdom for younger academics or younger entrepreneurs. And you probably have already gotten this question or you certainly will get it more and more. And that is how did you do it? You can tell us a secret of taking a research and commercializing it. And I understand you're still at the very beginning of that path, but what are some of the lessons you feel you've learned already being in academia for a good while now, and as you see the transition, perhaps of either a new life or a new path for your research commercial market, what are the sorts of things that you would do again, Ben, we can start with you and what are the things that you would not do again?

Ben Keselowsky: 20:03
So right now, what we're trying to do with this technology is very early. And so really the advice of team building is paramount finding the right people. We're still making those efforts. And so the Cade contest has been fantastic and it's motivated us to really push on that more and more, and to keep going out for more and more activities like that. And I think that's just expanding your contact base and trying to make more and more interactions until you find just the right match. So in this venture, we're still working on that. I'm trying to answer your specific question .

Richard Miles: 20:41
Okay. Anything else you want to dispense wisdom on? And just life advice, you know, you don't have to come up with the smart answers, but it's funny. Sometimes people have had either very positive or sort of horrific experiences along the way, but it sounds like you all have had a fairly stable, happy research careers to date.

Ben Keselowsky: 21:02
It's a lot of work, keeping your head up, having a group of people that you can rely on to keep you going and commiserate with is critical. So on the commercial side, I'm also a cofounder of a small company called One Vacs LLC. And they're still also working on finding the right business partners and investors and things like that. They have been quite successful with the people that have been working there. Greg Marshall, is he person there and he's been getting SBI. Ours is getting NIH funding through small business grants. So I think that that's a fantastic pathway that startup companies can take as well. But it's independent from finding the right business partners and you have to do both those things to be successful.

Richard Miles: 21:47
Greg how about you, aside from going out and getting banged up on the sports field as a path to advancement, what else would you share in terms of lessons learned?

Greg Hudalla: 21:54
I think a lot of us approach this with a vision of what we want to do. There's a finish line there. And I think the important part is figuring out how to move along that path. Really the first step in that process is identifying the technology. So I'll be the first one to admit when I started my academic career, I had no idea that this is where my research was going to go at galectin three and galactans are a family of proteins that I've studied in my research for a number of years now. But it really wasn't until a day that I remember very fondly of leaning against the door jam of Ben's office. And him kind of complaining to me and me complaining about various things. And he said, I've got this enzyme that I think is a really terrific candidate for therapeutic. I just don't know how to get it where I want it to go. And he said, could we do something like this? Could we modify it in this way or modified in that way? He's like all of my conventional approaches have tried and I just keep destroying the enzyme. I can't maintain its activity. And I was just kind of standing there daydreaming. And I remember saying, well, we work with on this family of carbohydrate binding proteins, nobody's really asked if we could use this as a way to localize it a protein at a site of interest. Let's take a shot at this and see what happens. And now, you know, we're three or four years down the road. We not only have demonstration that the concept works, but we've started moving it into developing this new drug that we think actually has potential to impact the quality of life of many people, the world over. And so for me, that's the thing that I would encourage people to not lose sight of the opportunity that's in front of you and listen to the people around you and take what you know, and try to find ways to move what you know, into new spaces. That's really what innovation is, right? It's not about inventing something new from scratch, right? I had a student a number of years ago, use the analogy of putting wheels on a suitcase for many years, we lugged suitcases around. So your cases are fantastic tool. As soon as someone put wheels on the suitcase, right? That innovation of taking two technologies that have been around for a very, very long time and blending them together. It revolutionized the way that we travel for me, that's at the crux of really doing something interesting and exciting and novel. It's not about finding something fundamentally new it's on some level, taking things that already exist and finding ways to repurpose them and opportunities to interact with amazing colleagues like Ben and the other people around me at UF have opened my eyes to opportunities that again, when I started my career, I didn't have the foresight and I didn't know that this was what my path would look like.

Richard Miles: 24:18
So you guys are gonna have to remember and write down these origin stories. Cause after you've sold Gator for billions of dollars, you both have yachts and multiple houses gonna need some sort of anchor of humility and touching Greg and Ben. I can already tell there's a great team dynamic here. I think you guys are gonna do quite well. And thank you very much for coming on Radio Cade, I hope to have you back as guests for an update.

Ben Keselowsky: 24:38
Thank you so much.

Greg Hudalla: 24:38
Yes. Thanks a lot.

Richard Miles: 24:40
I'm Richard Miles

Outro: 24:43
Radio Cade would like to thank the following people for their help and support Liz Gist of the Cade Museum for coordinating and vendor interviews. Bob McPeak of Heartwood Soundstage in downtown Gainesville, Florida for recording, editing and production of the podcasts and music theme. Tracy Collins for the composition and performance of the radio Cade theme song featuring violinist , Jacob Lawson and special. Thanks to the Cade museum for creativity and invention located in Gainesville, Florida.